Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling

• DOI: 10.1073/pnas.1414665111
• Publication Date: 2014-12-09T05:58:08Z
• Authors: Rimpy Dhingra; Victoria Margulets; Subir Roy Chowdhury; James Thliveris; Davinder Jassal; Paul Fernyhough; Gerald W. Dorn; Lorrie A. Kirshen...
• Keywords: 0303 health sciences; Antibiotics, Antineoplastic; Cell Death; Membrane Proteins; Mitochondria, Heart; 3. Good health; Electron Transport; Mitochondrial Proteins; Rats, Sprague-Dawley; Mice; 03 medical and health sciences; Doxorubicin; Animals; Myocytes, Cardiac; Cells, Cultured; Signal Transduction

Significance

We provide new, exciting evidence for a previously unidentified signaling pathway that mechanistically links mitochondrial respiratory chain defects to necrosis and heart failure induced by the chemotherapy agent doxorubicin (DOX). We specifically show that DOX disrupts protein complexes between the key respiratory chain proteins, including uncoupling protein 3 and cytochrome c oxidase, resulting in abnormal mitochondrial respiration and necrosis through a mechanism contingent on Bcl-2-like 19kDa-interacting protein 3 (Bnip3). Perhaps most compelling is our finding that inhibiting Bnip3 completely abrogated the cardiotoxic effects of DOX. These exciting findings have important clinical implications not only for preventing heart failure by targeting Bnip3 in cancer patients undergoing chemotherapy, but also for understanding the pathogenesis of other diseases in which mitochondrial function is compromised.